Zelen design clinical trials: why, when, and how Simon, Gregory E; Shortreed, Susan M; DeBar, Lynn L
Current controlled trials in cardiovascular medicine,
08/2021, Letnik:
22, Številka:
1
Journal Article
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In 1979, Marvin Zelen proposed a new design for randomized clinical trials intended to facilitate clinicians' and patients' participation. The defining innovation of Zelen's proposal was random ...assignment of treatment prior to patient or participant consent. Following randomization, a participant would receive information and asked to consent to the assigned treatment.
This narrative review examined recent examples of Zelen design trials evaluating clinical and public health interventions.
Zelen designs have often been applied to questions regarding real-world treatment or intervention effects under conditions of incomplete adherence. Examples include evaluating outreach or engagement interventions (especially for stigmatized conditions), evaluating treatments for which benefit may vary according to participant motivation, and situations when assignment to a control or usual care condition might prompt a disappointment effect. Specific practical considerations determine whether a Zelen design is scientifically appropriate or practicable. Zelen design trials usually depend on identifying participants automatically from existing records rather than by advertising, referral, or active recruitment. Assessments of baseline or prognostic characteristics usually depend on available records data rather than research-specific assessments. Because investigators must consider how exposure to treatments or interventions might bias ascertainment of outcomes, assessment of outcomes from routinely created records is often necessary. A Zelen design requires a waiver of the usual requirement for informed consent prior to random assignment of treatment. The Revised Common Rule includes specific criteria for such a waiver, and those criteria are most often met for evaluation of a low-risk and potentially beneficial intervention added to usual care. Investigators and Institutional Review Boards must also consider whether the scientific or public health benefit of a Zelen design trial outweighs the autonomy interests of potential participants. Analysis of Zelen trials compares outcomes according to original assignment, regardless of any refusal to accept or participate in the assigned treatment.
A Zelen design trial assesses the real-world consequences of a specific strategy to prompt or promote uptake of a specific treatment. While such trials are poorly suited to address explanatory or efficacy questions, they are often preferred for addressing pragmatic or policy questions.
A significant proportion of the overall cost of total hip arthroplasty (THA) results from the inpatient hospital stay following the procedure. Considering the substantial and increasing number of ...these procedures performed annually, shifting to an outpatient model of care where the patient is discharged home the same day as their surgery represents a potential for significant cost savings. The potential significant impact of an outpatient care model on constrained healthcare budgets and lack of high-quality evidence regarding its effectiveness warrants a rigorous comparative trial. The purpose of this prospective, randomized controlled trial is to evaluate outpatient care pathways for THA. Specifically, our objectives are to compare the rate of serious adverse events and estimate the cost-effectiveness of outpatient compared to standard inpatient THA.
We will include patients undergoing primary THA whom have an American Society of Anaesthetists status equal to or less than three, live within a 60-min driving distance of the institution and have an adult to accompany them home postoperatively and stay with them overnight. Consenting patients will be randomized to be discharged on the same day as surgery, as outpatients, or as inpatients according to standard of care (minimum of one night in hospital) using a modified Zelen consent model. The primary outcome measure is the incidence of serious adverse events at 30 days postoperative. Participants and their caregivers will complete secondary outcomes measures at each follow-up visit including patient-reported outcome measures and self-reported cost questionnaires.
This protocol is the first randomized trial to use blinding to evaluate outpatient THA compared to standard overnight stay and first to prospectively perform a full economic evaluation. It is also the first adequately powered trial to prospectively assess the safety of outpatient THA. Successful completion of this study could have the potential to provide clinical evidence for the role of outpatient THA in current practice.
This study was retrospectively registered on ClinicalTrials.gov ( NCT03026764 ) on March 9th, 2016.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
La obtención del consentimiento informado previo a la inclusión de los participantes en un ensayo clínico es un requisito ético-jurídico. En el diseño de Zelen la aleatorización es previa al ...consentimiento. En esta revisión se describen los estudios con aleatorización de Zelen y se analizan según lo establecido en España por la Ley 41/2002 Básica de Autonomía del Paciente, el RD 1090/2015 y la Ley 14/2007 de Investigación Biomédica. Se encontraron 78 estudios y se seleccionaron 23. El 61% eran “doble consentimiento”. En el 17,3% se justificaba el uso de este consentimiento porque incrementaba el reclutamiento de pacientes. El diseño de Zelen tiene varias limitaciones éticas. En los estudios revisados no aparecen argumentos claros para su utilización.
The perfect sampling method of
Kijima and Matsui (2006) for 2×
K contingency tables is extended to
2
×
⋯
×
2
×
K
tables. Based on this, a Metropolis sampling method is then proposed to implement ...Zelen's homogeneity test. Finally, an application is shown on gene expression data where cancer samples are compared to non-cancer samples across various tissues.
Abstract Background and Objective Although in effectiveness studies, the conventional randomized trial, in which informed consent is obtained before randomization, is the first choice, this design is ...not the panacea for all research questions. To counter contamination problems, prerandomization designs might be an alternative. Prerandomization implies that the randomization takes place before seeking informed consent, and because of this, prerandomization designs are controversial among ethicists, health lawyers, methodologists, and clinicians. However, in the Netherlands, these designs are becoming more accepted since the Dutch State Secretary of Health, Welfare and Sport decided that, under certain circumstances, prerandomization is admissible and not in conflict with the law. Results Based on well-defined indications and requirements, guidelines for the optimal application of prerandomization designs are presented. Designs in which prerandomization is used are outlined; methodological considerations useful when conducting trials using conventional designs or prerandomization designs are discussed, in addition to ethical and judicial aspects. Conclusion In certain situations, prerandomization designs have an essential contribution to achieve evidence-based medicine. Banning prerandomization a priori implies that information about the effectiveness of numerous public health and medical interventions will not be forthcoming. Therefore, every design should be based on a balance between maximizing the potential for patient autonomy and minimizing the bias caused by contamination. This balance cannot be reached by formulating general rules, but an independent group of experts, like members of research ethics committee (REC), should decide whether this balance is acceptable.
Marvin Zelen, a giant in the evolution of clinical trials, died of cancer on 15 November 2014. He was 87 years old. Professor Zelen was the Lemuel Shattuck Research Professor of Statistical Science, ...as well as a member of the Faculty of Arts and Sciences (Emeritus) at Harvard University.
Abstract Objective Assessing effects of lifestyle interventions in cancer patients has some specific challenges. Although randomization is urgently needed for evidence-based knowledge, sometimes it ...is difficult to apply conventional randomization (i.e., consent preceding randomization and intervention) in daily settings. Randomization before seeking consent was proposed by Zelen, and additional modifications were proposed since. We discuss four alternatives for conventional randomization: single and double randomized consent design, two-stage randomized consent design, and the design with consent to postponed information. Study Design and Setting We considered these designs when designing a study to assess the impact of physical activity on cancer-related fatigue and quality of life. We tested the modified Zelen design with consent to postponed information in a pilot. The design was chosen to prevent drop out of participants in the control group because of disappointment about the allocation. Results The result was a low overall participation rate most likely because of perceived lack of information by eligible patients and a relatively high dropout in the intervention group. Conclusion We conclude that the alternatives were not better than conventional randomization.
In the October 2014 publication of JAMA, Dr. Hinman and colleagues published the study “Acupuncture for Chronic Knee Pain： A Randomized Clinical Trial,” which concluded that in patients older than 50 ...years with moderate or severe chronic knee pain, neither laser nor needle acupuncture conferred benefit over sham for pain or function. Our findings do not support acupuncture for these patients.
Abstract Trials of many (> 2) treatments are common, particularly double-blind dose finding trials in Phase IIb where trials of four or more treatments are often seen. Such trials will almost ...certainly be conducted at multiple centres given the sponsor's desire to speed up the development program. When conducting such multicentre trials, the study team will always have to consider the question of whether the randomisation of the trial is to be stratified or balanced in some way by participating centre. In addressing this question there are three considerations: the impact on power, predictability and medication supply requirements. This paper will describe the use of alternative complex list based randomisation solutions that have been recently developed and implemented; two of the solutions have not previously been presented or published. The techniques maintain various degrees of control over treatment allocations at the centre and study as a whole; consequently the methods help with conserving supplies of medication. Simulation evidence will be presented for each technique.
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